Facile synthesis of sulfonyl amidines by 1,3-dipolar cycloaddition between 1-morpholinocycloalkenes and sulfonyl azides without catalyst

Article abstract of DOI:10.3987/COM-16-13503

Three new series of sulfonyl amidines were prepared by 1,3-dipolar cycloaddition reaction between 1-morpholinocycloalkenes and various substituted sulfonyl azides without catalyst at room temperature. This reaction yielded unstable bicyclic Δ² -1,2,3- Triazoline intermediates which rearranged themselves in situ into amidines by elimination of a nitrogen molecule. The reactions were performed under mild conditions and with moderate to good yields.

Full text of DOI:10.3987/COM-16-13503

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HETEROCYCLES, Vol. 92, No. 9, 2016
HETEROCYCLES, Vol. 92, No. 9, 2016, pp. 1614 - 1628. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 15th May, 2016, Accepted, 6th July, 2016, Published online, 15th July, 2016
DOI: 10.3987/COM-16-13503
FACILE SYNTHESIS OF SULFONYL AMIDINES BY 1,3-DIPOLAR
CYCLOADDITION BETWEEN 1-MORPHOLINOCYCLOALKENES AND
SULFONYL AZIDES WITHOUT CATALYST
Chiaa Adiche, Mohammed Hamadouche, and Douniazad El Abed*
Laboratory of Fine Chemistry (L.F.C), Chemistry Department, Faculty of Exact
and Applied Sciences, University of Oran 1, Ahmed BenBella, BP 1524 El
M’naouar, Oran, Algeria; E-mail: douniazed2000@yahoo.fr
Abstract – Three new series of sulfonyl amidines were prepared by 1,3-dipolar
cycloaddition reaction between 1-morpholinocycloalkenes and various substituted
sulfonyl azides without catalyst at room temperature. This reaction yielded
unstable bicyclic '2-1,2,3-triazoline intermediates which rearranged themselves in
situ into amidines by elimination of a nitrogen molecule. The reactions were
performed under mild conditions and with moderate to good yields.
INTRODUCTION
The amidines, nitrogen analogues of carboxylic acids, have fascinating chemical properties due to their
structures. They are widely used in the medicinal1 and synthetic chemistry.2 Indeed, the amidines featuring
very valuable biological properties are found in many bioactive natural products3 and are identified as
important pharmacophores.4 They are considered as important medical and biochemical agents as
anti-inflammatory,5 antimicrobial,6 antimalarial,7 antiparasitic8 and anti-cancer.5e,5f,9 They are versatile
building blocks for the synthesis of many different nitrogen-containing heterocycles:10 pyridines,11
pyrimidines,12 thiadiazoles,13 imidazoles, benzimidazoles14 and triazoles.15
NH2
Cl
HO
O
N
N
O
S
N
O
Me
O
O S O
N
O
O
N
N
Me
S
OMe
S
Me N
Me
O
O
N
O
O
N
O
N
H
H
I
III
II
IV
O
Figure 1. Sulfonyl amidines of biological interest

HETEROCYCLES, Vol. 92, No. 9, 2016
1615
The sulfonyl amidines, in particular, exhibit various important biological and pharmacological activities such
as antifungal I,16 antibacterial II,17 anti-resorptive III18 and antitumor IV19 (Figure 1).
Therefore, their synthesis has received much attention. Several routes of the amidine synthesis are
described in details in the literature. Amidines may be obtained from either amides,20 nitriles,
thioamides,21 sulfonamides,22 N,N-dibromosulfonamides or NBS/sulfonamides.23 They are also accessible
by reduction of amidoximes,24 imidoylation of amine with imidoyl chlorides.25 Furthermore, they are
prepared using the 1,3-dipolar cycloaddition reaction of imines with nitrile oxides.26 New protocols for
their preparation were recently developed as for example the direct coupling Cu-catalyzed, three
component reactions of a terminal alkyne, sulfonyl azide and amine.27 Moreover, the cycloaddition of
tosyl azide with aliphatic enamines using various solvents or in the absence of solvent gives rise to
sulfonyl amidines.28 Also, an easy synthesis of sulfonyl amidines from tertiary amines and various
substituted sulfonyl azides in the presence of FeCl3 as catalyst was developed successfully.29 However,
these methods have drawbacks such as long reaction times, low yields and the use of noxious solvents
such as benzene, methylene chloride, hexane or 1,4-dioxane.
On the other hand, to our knowledge, there are no previous works on the synthesis of sulfonyl amidines
from the cyclic enamines. Therefore, the aim of this study is the synthesis of sulfonyl amidines,
potentially bioactive, by 1,3-dipolar cycloaddition reaction between cyclic enamines and various sulfonyl
azides.
The sulfonyl amidines 3-5 were obtained by addition of sulfonyl azides on 1-morpholinocycloalkenes in a
highly stereoselective manner (Scheme 1).
Scheme 1. General synthetic route of sulfonyl amidines
1
The structures of sulfonyl amidines 3-5 were confirmed by a combination of H and 13C NMR
spectroscopy, mass spectroscopy and analysis, which gave good agreement with the proposed structures.
RESULTS AND DISCUSSION
The conditions of this cycloaddition reaction were optimized by varying the solvent. Thus different
solvents were used in testing the reaction of 1-morpholinocyclohexene 2a with tosyl azide 1b, at room
temperature and without the addition of a catalyst. The results of this screening are summarized in Table 1.

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HETEROCYCLES, Vol. 92, No. 9, 2016
Table 1. Optimization of the reaction conditionsa
O
N
solvent, rt
-N2
N
Ts N3
O
N
Ts
3b
2a
1b
Entry
Solvent
Time
Yield(%)b
1
2
3
4
5
6
7
8
9
DMF
MeOH
H2O
20 min
20 min
20 min
20 min
20 min
20 min
1 h
63
46
77
45
86
65
61
44
47
THF
Et2O
CH2Cl2
CHCl3
toluene
DMSO
10 h
20 min
aReaction conditions: tosylazide 1b (1 mmol, 1 equiv.), 1-morpholinocyclohexene 2a (1 mmol, 1
equiv.), and Et2O (5 mL). bIsolated yield after simple filtration followed by recrystallization in EtOH.
Among the solvents used, DMSO, THF, methanol and toluene gave the desired product in low yields
(Table 1, entries 9, 4, 2 and 8) whereas the reaction in diethyl ether induced a good yield (Table 1, entry
5). However, when the reaction was carried out in H2O, CH2Cl2, CHCl3 and DMF, the product was
obtained with yields of 77, 65, 61 and 63%, respectively.
Under the optimized reaction conditions, various sulfonyl azides and 1-morpholinocycloalkenes were examined.
The enamine 2a reacted with sulfonyl azides 1 at room temperature and in ether through 1,3-dipolar
cycloaddition and produced sulfonyl amidines 3a-n in moderate to good yields. As can be seen from Table 2, we
have utilized sulfonyl azides containing various substituents with the 1-morpholinocyclohexene.
Table 2. Sulfonyl amidines 3 prepared from 1-morpholinocyclohehexenea
Entry
Azide
Product
Time
Yield (%)b
81
O
O
O
S
N
Me
S
N3
1
20 min
N
Me
O
O
3a
O
O
S
O
N
Me
N3
2
20 min
86
N
S
Me
3b
O
O
O
O2N
O
NO2
O
N
3
20 min
71
N
S
S
N3
O
O
3c

HETEROCYCLES, Vol. 92, No. 9, 2016
1617
Table 2. (continued)
O
O2N
NO2
O
S
O
N
4 h
60
4
N3
N
S
O
O
3d
O
O
O
N
O2N
S
N3
20 min
1 h
82
43
5
6
N
S
NO2
O
O
3e
O
O
S
O
S
N
N3
N
O
O
3f
O
O
S
O
N
N3
1 h
1 h
43
58
83
76
67
7
8
N
S
O
O
3g
O
O
O
O
O
O
O
S
N
N
N
N
N
F
S
N3
N3
N3
N3
F
N
N
N
N
N
O
O
3h
O
O
Cl
Br
I
S
20 min
20 min
4 h
9
S
Cl
O
O
3i
O
S
O
S
10
11
12
Br
O
O
3j
O
O
S
S
I
O
O
3k
O
S
O
S
24 h
67
35
55
N3
O
O
3l
N3
O
N
O
N
S
O
O
S
O
S O
O
1 h
13
O
N
N3
N
S
O
O
3m
O
O
S
O
N
N3
4 h
14
N
S
S
O
S
O
3n
aReaction conditions: sulfonyl azide 1 (1 mmol, 1 equiv.), 1-morpholinocyclohexene 2a (1 mmol, 1 equiv.), and
Et2O (5 mL). bIsolated yield after simple filtration followed by recrystallization in EtOH.
cBenzene-1,3-disulfonyl azide 1 (1 mmol, 1 equiv.), 1-morpholinocyclohexene 2 (2.0 mmol, 2.0 equiv.).
This reaction carried out with the 1-morpholinocyclohexene 2a provided access to the sulfonyl amidines 3 which
were produced with yields varying from 35 to 86% in a very short reaction time. The best yields were obtained

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HETEROCYCLES, Vol. 92, No. 9, 2016
from the tosyl azide and the sulfonyl azides 1a, 1e, 1i, (Table 2, entries 2, 1, 5 and 9) as 86, 81, 82 and 83%,
respectively. The sulfonyl azides with 4-fluoro, 4-bromo or 4-iodo substrate showed good reactivity and
generated the corresponding product with 58, 76 and 67% yields (Table 2, entries 8, 10 and 11), respectively.
The bulky and strongly electron-donating group of the 2,4,6-tri-isopropylbenzene sulfonyl azide (Table 2, entry
12) gave the desired product in a longer reaction time with a 67% yield. It should be noted that the reaction can
be performed not only with electron-donating groups, but also with electron-withdrawing groups (Table 2,
entries 3-5). According to the results, the nitro substituents on the aromatic rings of the sulfonyl azides have a
strong influence on the formation of sulfonyl amidines. It is observed that the para position substituents have a
positive influence on the yield. For example, p-NO2 sulfonyl azide leads to sulfonyl amidine 3e with 82% yield.
Similarly, with benzenesufonyl azide and thiophene-2-sulfonyl azide, the formation of 3f and 3n is achieved
(Table 2, entries 6 and 14), respectively. However, with the 4-ethylbenzensulfonyl azide and
benzene-1,3-disulfonyl azide (Table 2, entries 7 and 13), the yields do not exceed 43%.
Then, we investigated the reactivity of 1-morpholinocycloheptene with sulfonyl azides 1. The results obtained
for the synthesis of sulfonyl amidines 4 are given in Table 3.
Table 3. Sulfonyl amidines 4 prepared from 1-morpholinocycloheptenea
Entry
Azide
Product
Time
Yield (%)b
O
O
S
O
N
Me
N3
1
24
71
N
S
Me
4a
O
O
O
O2N
O
NO2
O
N
2
3
4
48
24
72
25
41
30
N
S
S
N3
O
O
4b
O
O
S
O
N
O2N
N3
N
S
NO2
4c
O
O
O
O
S
O
N
N3
N
S
O
O
4d
O
O
S
O
N
N3
5
6
72
72
11
61
N
S
O
O
4e
O
O
S
O
N
N3
N
S
S
S
O
O
4f
aReaction conditions: sulfonyl azide 1 (1 mmol, 1 equiv.), 1-morpholinocycloheptene 2b (1 mmol, 1
equiv.), and Et2O (5 mL). bIsolated yield after simple filtration followed by recrystallization in EtOH.

HETEROCYCLES, Vol. 92, No. 9, 2016
1619
Under the same conditions, the sulfonyl azides 1 were added to the 1-morpholinocycloheptene 2b to provide
products 4a-f. This reaction sequence required a much longer reaction time for the formation of sulfonyl
amidines 4, with yields ranging from 11 to 71%. It was observed that the ethyl electron-donating group in the
para position on the phenyl ring required a much longer reaction time and resulted in a lower yield than the
one associated with the methyl substituent (Table 3, entries 1 and 5). However, NO2 electron-withdrawing
group in the para position lead to the corresponding sulfonyl amidines 4c with 41% yield (Table 3, entry 3).
Finally, we examined the reaction of 1-morpholinocyclooctene with sulfonyl azide 1 as shown on Table 4.
Table 4. Sulfonyl amidines 5 prepared from 1-morpholinocyclooctenea
Entry
Azide
Product
Time
Yield (%)b
64
O
O
S
O
N
N
S
Me
5a
Me
N3
1
20 min
O
O
O
O2N
NO2
O
O
N
N
S
2
3
4
5
20 min
24 h
98
71
92
69
S
N3
O
O
5b
O
NO2
O2N
O
N
O
N
S
S
N3
O
O
5c
O
O
O
N
O2N
S
N3
N
S
NO2
5d
20 min
20 h
O
O
O
O
S
O
S
N
N
N3
O
O
5e
O
O
S
O
N
N
S
N3
6
7
8
9
24 h
48 h
1 h
85
64
62
62
O
O
5f
O
O
O
S
N
N
F
S
N3
N3
N3
F
O
O
5g
O
O
O
O
S
N
N
N
Cl
S
Cl
O
O
5h
O
S
O
S
N
Br
Br
24 h
O
O
5i

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HETEROCYCLES, Vol. 92, No. 9, 2016
Table 4. (continued)
O
O
S
O
N
N
S
I
N3
I
10
4 h
78
51
O
O
5j
O
O
S
O
S
N
N
N3
11
48 h
S
S
O
O
5k
aReaction conditions: sulfonyl azide 1 (1 mmol, 1 equiv.), 1-morpholinocyclooctene 2c (1 mmol, 1 equiv.),
and Et2O (5 mL). bIsolated yield after simple filtration followed by recrystallization in EtOH.
The sulfonyl amidines 5a-k could also be accessed from the 1-morpholinocyclooctene 2c. This reaction
sequence was performed under the same conditions as the previous reactions. The use of the
ortho-nitrobenzenesulfonyl azide gave a much higher yield (98%) than that of the para- and
meta-nitrobenzenesulfonyl azides (Table 4, entries 2-4). The desired sulfonyl amidines were formed with
a high yield when using various sulfonyl azides bearing different electron-donating groups on the phenyl
ring. For example, p-ethyl sulfonyl azide formed the corresponding sulfonyl amidine 5f with 85% yield
while with p-methyl, the yield did not exceed 64% (Table 4, entries 6 and 1). The reaction could also be
carried out with halogenated groups as substituent on the phenyl ring to produce the corresponding
sulfonyl amidines 5 g-j with yields ranging from 62 to 78% (Table 4, entries 7-10). However, there is a
drastic loss of performance when thiophene-2-sulfonyl azide is used (Table 4, entry 11).
The results, together studies in literature,30 lead us to propose the following mechanism for the formation
of sulfonyl amidines (Scheme 2).
Scheme 2. Proposed Reaction Mechanism
The cyclic enamines 2 react with the sulfonyl azides 1 through a 1,3-dipolar cycloaddition to produce
unstable bicyclic '2-1,2,3-triazoline intermediates which by nitrogen loss and ring contraction of the
enamines provide the expected sulfonyl amidines 3-5. It should be noted that the reaction of
1-morpholinocyclohexene led to good yields. The nature of the sulfonyl azide substituents and the
enamine ring sizes has a great influence on the yield and time of the reaction.

HETEROCYCLES, Vol. 92, No. 9, 2016
1621
In conclusion, we have developed a catalyst-free, simple and efficient protocol for the transformation of
cyclic enamines and sulfonyl azides into sulfonyl amidines. The reactions performed in diethyl ether at
room temperature did not require any special precautions. The products were obtained under mild
reaction conditions with moderate to good yields. This approach is economically attractive due to the easy
access to several sulfonyl amidines.
EXPERIMENTAL
All reagents and solvents were purchased from commercial suppliers and were used without further
1
purification. Melting points were determined with a Kofler apparatus and they are uncorrected. H (300
13
MHz) and C (75 MHz), NMR spectra were recorded using a Bruker AC300 spectrometer using CDCl3
or DMSO. Infrared spectra (IR) were taken on a Nicolet IRFT IR 200 spectrometer, and were obtained as
solids in KBr. Peaks are reported in cm-1. High-resolution mass spectra (MS) were obtained at 2.8
kV electrospray voltage, 20 V voltage orifice, and flow of nebulizing gas (nitrogen): 100 L/h.
Atmospheric pressure ionization (API) and electrospray (ESI) mass spectra were recorded on a SYNAPT
G2 HDMS spectrometer (Waters). Elemental analyses were performed by apparatus CHNS.
General procedure for preparing cyclic enamines and sulfonyl azides: The enamines 2a-c were
prepared by a method reported in the literature.31 Sulfonyl azides 1 were prepared by the corresponding
sulfonyl chlorides according to literature.32
General procedure for preparing sulfonyl amidines: To a stirred solution of sulfonyl azide 1 (1 mmol,
1 equiv.) in Et2O (5 mL) and 1-morpholinocycloalkene 2 (1 mmol, 1 equiv.) was added successively, the
mixture was kept at room temperature. The color of the reaction mixture turned light yellow, after that a
precipitate was formed. The precipitate was collected by simple filtration followed byrecrystallization in EtOH.
The products 3-5 together with their physical constants are listed below.
N-(Cyclopentyl(morpholino)methylene)methanesulfonamide (3a). White solid. mp 154-156 °C; Yield
81%; 1H NMR (300 MHz, CDCl3) δ ppm: 1.65-1.84 (m, 4H), 2.16-2.23 (m, 2H), 2.91-2.94 (m, 2H), 3.00
13
(s, 3H), 3.61-3.71 (m, 8H), 3.93-4.05 (m, 1H); C NMR (75 MHz, CDCl3) δ ppm: 27.11, 30.76, 43.31,
44.24, 47.40, 66.80, 170.45. Anal. Calcd for C10H20SO3N2 (%): C 48.36, H 8.12, N 11.28, S 12.91. Found
C 48.43, H 7.74, N 10.43, S 12.12.
N-(Cyclopentyl(morpholino)methylene)-4-methylbenzenesulfonamide (3b).33 White solid. mp
148-150 °C; Yield 86%; IR ν (cm-1): 1535 (C=N), 1351 (SO2), 1258 (C-N), 1080 (C-O); 1H NMR (300 MHz,
CDCl3) δ ppm: 1.66-1.77 (m, 6H), 2.02-2.10 (m, 2H), 2.37 (s, 3H), 3.61-3.68 (m, 8H), 4.00-4.13 (m, 1H), 7.23
(d, J=7.93 Hz, 2H), 7.77 (d, J=8.12 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ ppm: 21.35, 26.60, 30.27, 42.39,
47.03, 66.32, 126.05, 129.01, 141.37, 141.74, 170.21.
N-(Cyclopentyl(morpholino)methylene)-2-nitrobenzenesulfonamide (3c). Yellow solid. mp

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HETEROCYCLES, Vol. 92, No. 9, 2016
126-128 °C; Yield 71%; IR ν (cm-1): 1547 (C=N), 1351 (SO2), 1531 (NO2), 1224 (C-N), 1032 (C-O); 1H
NMR (300 MHz, CDCl3) δ ppm: 1.68-1.80 (m, 6H), 2.10-2.17 (m, 2H), 3.60-3.71 (m, 8H), 3.88-4.00 (m,
13
1H), 7.61-7.68 (m, 3H), 8.17-8.20 (m, 1H); C NMR (75 MHz, CDCl3) δ ppm: 26.59, 30.28, 43.18,
47.34, 66.37, 123.88, 128.80, 131.66, 132.20, 136.79, 147.58, 170.36.
N-(Cyclopentyl(morpholino)methylene)-3-nitrobenzenesulfonamide (3d). White solid. mp 118-120 °C;
1
Yield 60%; H NMR (300 MHz, DMSO) δ ppm: 1.59-1.90 (m, 6H), 3.35 (m, 6H), 3.63 (m, 4H), 3.75-3.83
(m, 1H), 7.85 (t, J=8.02 Hz, 1H), 8.24 (d, J=8.07, Hz, 1H), 8.40-8.45 (m, 2H); 13C NMR (75 MHz, DMSO) δ
ppm: 26.54, 30.22, 42.90, 47.93, 66.15, 120.56, 126.64, 131.58, 132.28, 146.46, 148.14, 170.27.
N-(Cyclopentyl(morpholino)methylene)-4-nitrobenzenesulfonamide (3e). Orange solid. mp
150-152 °C; Yield 82%; IR ν (cm-1): 1605 (C=N), 1523 (NO2), 1348 (SO2), 1221 (C-N), 1028 (C-O); 1H
NMR (300 MHz, CDCl3) δ ppm: 1.77-1.83 (m, 6H), 2.15-2.22 (m, 2H), 3.65-3.74 (m, 8H), 3.98-4.07 (m,
1H), 8.11 (d, J=8.88 Hz, 2H), 8.33 (d, J=8.88 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ ppm: 26.67, 30.53,
43.36, 66.33, 123.88, 127.39, 139.32, 141.37, 170.57.
N-(Cyclopentyl(morpholino)methylene)benzenesulfonamide (3f). White solid. mp 140-142 °C; Yield
47%; IR ν (cm-1): 1535 (C=N), 1345 (SO2), 1224 (C-N), 1033 (C-O); 1H NMR (300 MHz, CDCl3) δ ppm:
1.63-1.78 (m, 6H), 2.04-2.11 (m, 2H), 3.61-3.70 (m, 8H), 4.01-4.13 (m, 1H), 7.42-7.48 (m, 3H),
13
7.88-7.92 (dd, J=1.93 Hz, J=6.05 Hz, 2H); C NMR (75 MHz, CDCl3) δ ppm: 26.64, 30.32, 42.57,
47.10, 66.35, 126.07, 128.46, 131.32, 144.16, 170.35.
N-(Cyclopentyl(morpholino)methylene)-4-ethylbenzenesulfonamide (3g). White solid. mp
1
114-116 °C; Yield 43%; IR ν (cm-1): 1535 (C=N), 1351 (SO2), 1219 (C-N), 1031 (C-O); H NMR (300
MHz, CDCl3) δ ppm: 1.26 (t, J=7.61 Hz, 3H), 1.70-1.80 (m, 6H), 2.09-2.14 (m, 2H), 2.67-2.74
(quadruplet, J=7.61 Hz, J=7.6 Hz, 2H), 3.63-3.71 (m, 8H), 4.05-4.17 (m, 1H), 7.29 (d, J=8.35 Hz, 2H),
13
7.83 (d, J=7.82 Hz, 2H); C NMR (75 MHz, CDCl3) δ ppm: 15.29, 26.71, 28.76, 30.37, 42.51, 47.09,
66.42, 126.24, 127.98, 141.59, 148.06, 170.33.
N-(Cyclopentyl(morpholino)methylene)-4-fluorobenzenesulfonamide (3h). White solid. mp
1
148-150 °C; Yield 58%; IR ν (cm-1): 1538 (C=N), 1344 (SO2), 1224 (C-N), 1033 (C-O), 1138 (C-F); H
NMR (300 MHz, CDCl3) δ ppm: 1.65-1.79 (m, 6H), 2.07-2.15 (m, 2H), 3.61-3.71 (m, 8H), 3.99-4.11 (m,
1H), 7.12 (t, J= 8.66 Hz, 2H), 7.89-7.93 (dd, J=3.76 Hz, J=5.14 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
ppm: 26.66, 30.37, 42.71, 47.18, 66.33, 115.38, 115.67, 128.73, 140.36, 162.56, 170.32.
4-Chloro-N-(cyclopentyl(morpholino)methylene)benzenesulfonamide (3i). White solid. mp
1
134-136 °C; Yield 83%; IR ν (cm-1): 1538 (C=N), 1351 (SO2), 1219 (C-N), 1034 (C-O), 574 (C-Cl); H
NMR (300 MHz, CDCl3) δ ppm: 1.65-1.79 (m, 6H), 2.08-2.16 (m, 2H), 3.61-3.71 (m, 8H), 3.97-4.09 (m,
1H), 7.42 (d, J=8.62 Hz, 2H), 7.85 (d, J=8.71 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ ppm: 26.65, 30.39,
42.79, 47.20, 66.33, 127.61, 128.70, 137.55, 142.76, 170.33. Anal. Calcd for C16H21SO3ClN2 (%): C

HETEROCYCLES, Vol. 92, No. 9, 2016
1623
54.17, H 5.91, N 7.81, S 8.79. Found C 54.19, H 5.92, N 7.78, S 8.68; HRMS (ESI) calcd. for
C16H21SO3ClN2 ([M+H]+) 357.1034. Found 357.1034.
4-Bromo-N-(cyclopentyl(morpholino)methylene)benzenesulfonamide (3j). White solid. mp
1
166-168 °C; Yield 76%; H NMR (300 MHz, CDCl3) δ ppm: 1.65-1.80 (m, 6H), 2.08-2.16 (m, 2H),
13
3.61-3.71 (m, 8H), 3.97-4.09 (m, 1H), 7.58 (d, J=8.62 Hz, 2H), 7.77 (d, J=8.62 Hz, 2H); C NMR (75
MHz, CDCl3) δ ppm: 26.64, 30.38, 42.79, 47.19, 66.31, 125.97, 127.75, 131.67, 143.25, 170.34.
N-(Cyclopentyl(morpholino)methylene)-4-iodobenzenesulfonamide
(3k).
White
solid.
mp
1
220-222 °C; Yield 67%; IR ν (cm-1): 1529 (C=N), 1346 (SO2), 1219 (C-N), 1027 (C-O), 579 (C-I); H
NMR (300 MHz, CDCl3) δ ppm: 1.65-1.79 (m, 6H), 2.08-2.16 (m, 2H), 3.60-3.70 (m, 8H), 3.96-4.09 (m,
1H), 7.63 (d, J=8.44 Hz, 2H), 7.79 (d, J=8.44 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ ppm: 26.72, 30.45,
42.86, 47.20, 66.39, 98.32, 127.76, 137.71, 143.97, 170.40.
N-(Cyclopentyl(morpholino)methylene)-2,4,6-triisopropylbenzenesulfonamide (3l). White solid. mp
1
128-130 °C; Yield 67%; H NMR (300 MHz, CDCl3) δ ppm: 1.13-1.29 (m, 18H), 1.43-1.66 (m, 6H),
2.18-2.37 (m, 2H), 3.39-3.55 (m, 3H), 3.57-3.78 (m, 8H), 4.31-4.40 (m, 1H), 7.10 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ ppm: 23.67, 24.69, 26.51, 29.45, 29.93, 34.09, 41.72, 66.38, 123.20, 137.34, 148.75, 151.46, 169.76.
(E)-N1,N3-Bis(cyclopentyl(morpholino)methylene)benzene-1,3-disulfonamide (3m). White solid. mp
180-182 °C; Yield 35%; IR ν (cm-1): 1529 (C=N), 1353 (SO2), 1220 (C-N), 1030 (C-O); 1H NMR (300 MHz,
CDCl3) δ ppm: 1.25-1.31 (m, 2H), 1.59-1.81 (m, 10H), 2.06-2.25 (m, 4H), 3.00 (t, J=4.61 Hz, 2H), 3.25-3.27
(m, 2H), 3.62-3.70 (m, 12H), 3.93-4.05 (m, 2H), 7.53-7.66 (m, 1H), 8.02-8.11 (dd, J=1.74 Hz, J=7.79 Hz, 2H),
8.46 (s, 1H); 13C NMR (75 MHz, CDCl3) δ ppm: 26.73, 30.44, 42.79, 64.65, 66.41, 124.50, 128.86, 129.02,
144.87, 170.52. HRMS (ESI) calcd. for C26H38N4O6S2 ([M+H]+) 567.2306. Found 567.2306.
N-(Cyclopentyl(morpholino)methylene)thiophene-2-sulfonamide (3n). White solid. mp 120-122 °C;
Yield 55%; IR ν (cm-1): 1539 (C=N), 1343 (SO2), 1223 (C-N), 1031 (C-O); 1H NMR (300 MHz, CDCl3)
δ ppm: 1.69-1.76 (m, 6H); 2.04-2.11 (m, 2H); 3.65-3.69 (m, 8H), 3.95-4.09 (m, 1H); 7.98 (dd, J=1.92 Hz,
J=3.85 Hz, 1H); 7.44 (dd, J=1.28 Hz, J=3.76 Hz, 1H), 7.56 (dd, J=1.28 Hz, J=2.38 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ ppm: 26.71, 30.42, 42.54, 47.37, 66.47, 126.69, 129.57, 130.00, 146.04, 170.40. Anal.
Calcd for C14H20S2O3N2 (%): C 51.56, H 6.14, N 8.47, S 19.42. Found C 51.55, H 6.12, N 8.45, S 19.30;
HRMS (ESI) calcd. for C14H20S2O3N2 ([M+H]+) 329.0988. Found 329.0991.
N-(Cyclohexyl(morpholino)methylene)-4-methylbenzenesulfonamide (4a). White solid. mp
110-112 °C; Yield 71%; 1H NMR (300 MHz, CDCl3) δ ppm: 1.58-1.90 (m, 8H), 2.34-2.42 (m, 2H), 2.43 (s,
3H), 2.91 (m, 2H), 3.69-3.75 (m, 6H), 3.95-3.99 (m, 1H), 7.31 (d, J=8.12 Hz, 2H), 7.73 (d, J=8.30 Hz, 1H),
7.82 (dd, J=2.45 Hz, J=8.12 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ ppm: 21.88, 23.94, 26.43, 27.15, 28.69,
33.63, 41.24, 46.71, 51.10, 62.23, 67.03, 126.51, 127.41, 129.47, 130.10, 137.06, 143.95, 209.19.
N-(Cyclohexyl(morpholino)methylene)-2-nitrobenzenesulfonamide (4b). Orange solid. mp

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HETEROCYCLES, Vol. 92, No. 9, 2016
1
140-142 °C; Yield 25%; H NMR (300 MHz, CDCl3) δ ppm: 1.20-1.84 (m, 10H), 3.44-3.51 (dd, J=6.97
13
Hz, J=7.15 Hz, 2H), 3.70-3.84 (m, 6H), 3.85-3.94 (m, 1H), 7.65-7.78 (m, 3H), 8.12-8.26 (m, 1H); C
NMR (75 MHz, CDCl3) δ ppm: 15.28, 24.83, 25.04, 26.16, 28.19, 34.87, 54.83, 65.86, 123.94, 125.14,
129.35, 131.82, 133.44, 136.03, 147.73.
N-(Cyclohexyl(morpholino)methylene)-4-nitrobenzenesulfonamide (4c). Yellow solid. mp
1
134-136 °C; Yield 41%; H NMR (300 MHz, CDCl3) δ ppm: 1.25-1.85 (m, 8H), 2.06-2.19 (m, 2H),
2.35-2.54 (m, 2H), 2.90 (m, 2H), 3.62-3.72 (m, 4H), 4.03-4.07 (m, 1H), 8.01 (d, J=8.78 Hz, 2H), 8.33 (t,
13
J=8.88 Hz, 2H); C NMR (75 MHz, CDCl3) δ ppm: 23.54, 26.72, 28.91, 33.34, 40.86, 62.15, 124.39,
128.23, 143.81, 145.92, 146.79.
N-(Cyclohexyl(morpholino)methylene)benzenesulfonamide (4d). White solid. mp 180-182 °C; Yield
30%; IR ν (cm-1): 1539 (C=N), 1349 (SO2), 1217 (C-N), 1022 (C-O); 1H NMR (300 MHz, CDCl3) δ ppm:
1.11-1.37 (m, 2H), 1.51-1.87 (m, 8H), 3.67-3.71 (m, 8H), 3.73-3.75 (m, 1H), 7.41-7.49 (m, 3H),
7.90-7.93 (m, 2H); 13C NMR (75 MHz, CDCl3) δ ppm: 25.38, 25.96, 28.21, 43.47, 47.66, 66.56, 126.02,
128.44, 131.27, 144.34, 170.14.
N-(Cyclohexyl(morpholino)methylene)-4-ethylbenzenesulfonamide (4e). White solid. mp 168-170 °C;
1
Yield 11%; H NMR (300 MHz, CDCl3) δ ppm: 1.25 (t, J=7.56 Hz, 3H), 1.30-1.39 (m, 2H), 1.50-1.89
(m, 8H), 2.67-2.74 (quadruplet, J=7.61 Hz, J=7.61 Hz, 2H), 3.69-3.74 (m, 8H), 3.74-3.76 (m, 1H),
13
7.28-7.30 (d, J=6.51 Hz, 2H), 7.82-7.85 (d, J=8.25 Hz, 2H); C NMR (75 MHz, CDCl3) δ ppm: 15.29,
25.55, 26.09, 28.39, 28.76, 43.51, 47.74, 66.68, 126.26, 127.96, 141.88, 148.03, 170.63.
N-(Cyclohexyl(morpholino)methylene)thiophene-2-sulfonamide (4f). White solid. mp 160-162 °C;
Yield 61%; IR ν (cm-1): 1537 (C=N), 1348 (SO2), 1224 (C-N), 1015 (C-O); 1H NMR (300 MHz, CDCl3)
δ ppm: 1.19-1.28 (m, 2H), 1.53-1.80 (m, 6H), 2.41-2.50 (m, 2H), 3.70-3.62 (m, 8H), 4.00-4.04 (m, 1H),
13
6.92-7.01 (m, 2H), 7.49-7.52 (m, 1H); C NMR (75 MHz, CDCl3) δ ppm: 25.52, 26.09, 28.36, 43.60,
47.96, 66.70, 126.69, 129.60, 129.99, 146.24, 170.20.
N-(Cycloheptyl(morpholino)methylene)-4-methylbenzenesulfonamide (5a). White solid. mp 96-97 °C;
Yield 64%; IR ν (cm-1): 2912 (C–H), 1531 (C=N), 1431 (SO2); 1H NMR (300 MHz, CDCl3) δ ppm: 1.26-1.36
(m, 2H), 1.49-1.72 (m, 10H), 2.38 (s, 3H), 3.57-3.71 (m, 8H), 4.22-4.30 (m, 1H), 7.23 (d, J=8.3 Hz, 2H), 7.69
(d, J=8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ ppm: 21.89, 24.71, 26.42, 27.82, 28.37, 28.65, 30.47, 39.37,
51.95, 67.34, 127.40, 129.78, 137.88, 143.52, 146.62.
N-(Cycloheptyl(morpholino)methylene)-2-nitrobenzenesulfonamide (5b). White solid. mp 110-112 °C;
Yield 98%; IR ν (cm-1): 1551 (NO2), 1533 (C=N), 1358 (SO2), 1260 (C-N), 1067 (C-O); 1H NMR (300 MHz,
CDCl3) δ ppm: 1.48-1.75 (m, 10H), 2.17-2.34 (m, 2H), 3.61-3.75 (m, 8H), 3.77-3.81 (m, 1H), 7.67-7.76 (m,
13
2H), 7.85-7.90 (m,1H), 8.13-8.17 (m, 1H); C NMR (75 MHz, CDCl3) δ ppm: 22.96, 24.87, 25.74, 26.86,
27.88, 30.12, 31.54, 50.56, 66.80, 125.03, 129.12, 130.78, 133.44, 134.58, 145.99, 147.90.

HETEROCYCLES, Vol. 92, No. 9, 2016
1625
N-(Cycloheptyl(morpholino)methylene)-3-nitrobenzenesulfonamide (5c). White solid. mp
156-158 °C; Yield 71%; IR ν (cm-1): 1605 (C=N), 1533 (NO2), 1338 (SO2), 1219 (C-N), 1027 (C-O);
1
Yield 71%; H NMR (300 MHz, CDCl3) δ ppm: 1.38-1.56 (m, 8H), 2.12-2.17 (m, 2H), 2.38-2.46 (m,
4H), 3.63-3.73 (m, 4H), 3.92-3.99 (m, 1H), 7.73-7.78 (m, 1H), 8.18-8.21 (m, 1H), 8.37-8.43 (m, 1H),
13
8.63 (s, 1H); C NMR (75 MHz, CDCl3) δ ppm: 22.89, 24.60, 25.83, 26.63, 27.80, 31.40, 50.65, 67.15,
122.14, 127.10, 129.26, 130.45, 132.57, 134.35, 148.22.
N-(Cycloheptyl(morpholino)methylene)-4-nitrobenzenesulfonamide (5d). White solid. mp 156-158 °C;
Yield 92%; IR ν (cm-1): 1607 (C=N), 1530 (NO2), 1339 (SO2), 1264 (C-N), 1009 (C-O); 1H NMR (300 MHz,
CDCl3) δ ppm: 1.25-1.75 (m, 10H), 1.99-2.17 (m, 2H), 2.36-2.47 (m, 2H), 3.63-3.70 (m, 6H), 4.32-4.38 (m,
1H), 8.00-8.11 (m, 2H), 8.32 (t, J=8.92 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ ppm: 24.65, 25.84, 26.62, 27.36,
27.82, 28.31, 30.26, 50.60, 51.67, 66.39, 67.09, 123.89, 124.07, 124.21, 127.44, 128.23, 129.19, 147.22.
N-(Cycloheptyl(morpholino)methylene)benzenesulfonamide (5e). White solid. mp 120-122 °C; Yield
69%; IR ν (cm-1): 1530 (C=N), 1352 (SO2), 1161 (C-N), 1089 (C-O); 1H NMR (300 MHz, CDCl3) δ ppm:
1.22-2.04 (m, 12H), 2.21-2.28 (m, 1H), 2.71-2.78 (m, 1H), 3.57-3.71 (m, 6H), 4.24-4.32 (m, 1H),
13
7.42-7.52 (m, 3H), 7.81-7.83 (dd, J=2.02 Hz, J=5.96 Hz, 1H), 7.90-7.93 (m, 1H); C NMR (75 MHz,
CDCl3) δ ppm: 24.25, 25.99, 27.39, 27.97, 28.19, 30.15, 38.99, 43.51, 51.46, 66.47, 66.93, 126.17,
126.93, 128.52, 128.79, 132.38, 140.34, 146.50.
N-(Cycloheptyl(morpholino)methylene)-4-ethylbenzenesulfonamide (5f).
White solid. mp
1
138-140 °C; Yield 85%; IR ν (cm-1): 1537 (C=N), 1350 (SO2), 1218 (C-N), 1017 (C-O); H NMR (300
MHz, CDCl3) δ ppm: 1.21-1.27 (t, J=7.61 Hz, 3H), 1.34-1.81 (m, 10H), 1.99-2.15 (m, 2H), 2.24-2.30 (m,
2H), 2.66-2.73 (quadruplet, J=7.61 Hz, J=7.6 Hz, 2H), 3.69-3.72 (m, 6H), 4.25-4.32 (m, 1H), 7.26-7.31
13
(d, J=7.98 Hz, 2H), 7.72-7.75 (d, J=8.25 Hz, 2H); C NMR (75 MHz, CDCl3) δ ppm: 15.32, 24.30,
26.04, 27.45, 27.99, 28.78, 30.08, 43.40, 50.52, 51.50, 66.52, 66.98, 127.14, 128.37, 137.62, 147.19,
149.36.
N-(Cycloheptyl(morpholino)methylene)-4-fluorobenzenesulfonamide (5g). White solid. mp
146-148 °C; Yield 64%; IR ν (cm-1): 1588 (C=N), 1331 (SO2), 1227 (C-N), 1152 (C-F), 1023 (C-O); 1H NMR
(300 MHz, CDCl3) δ ppm: 1.20-1.71 (m, 12H), 2.29 (m, 4H), 3.59-3.73 (t, J=6.11 Hz, 2H), 4.24-4.31 (m, 1H),
13
7.10-7.18 (dd, J=8.53 Hz, J=8.71 Hz, 2H), 7.81-7.87 (m, 2H); C NMR (75 MHz, CDCl3) δ ppm: 22.84,
24.68, 25.91, 26.68, 27.83, 31.50, 39.01, 50.58, 51.57, 67.14, 116.02, 116.32, 129.60, 134.03, 146.00, 163.28.
4-Chloro-N-(cycloheptyl(morpholino)methylene)benzenesulfonamide (5h). White solid. mp
136-138 °C; Yield 62%; IR ν (cm-1): 1476 (C=N), 1365 (SO2), 1237 (C-N), 1024 (C-O), 655 (C-Cl); 1H NMR
(300 MHz, CDCl3) δ ppm: 1.24-1.77 (m, 10H), 1.97-2.16 (m, 2H), 2.26-2.32 (m, 2H), 2.47 (t, J= 6.16 Hz, 1H),
2.74-2.81 (m, 1H), 3.58-3.73 (m, 4H), 4.25-4.33 (m, 1H), 7.44 (t, J=8.48 Hz, 2H), 7.75-7.78 (dd, J=6.51 Hz,
J=2.11 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ ppm: 24.25, 26.07, 26.66, 27.40, 29.99, 31.47, 39.00, 50.58,

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HETEROCYCLES, Vol. 92, No. 9, 2016
51.56, 66.92, 67.12, 128.42, 129.06, 129.20, 138.83, 139.06, 145.90. Anal. Calcd for C18H25SO3ClN2 (%): C
56.40, H 6.51, N 7.26, S 8.06. Found 56.62; H, 6.54; N, 7.27; S, 8.18. HRMS (ESI) calcd. for C18H25SO3ClN2
([M+H]+) 385.1347. Found 385.1347.
4-Bromo-N-(cycloheptyl(morpholino)methylene)benzenesulfonamide (5i). White solid. mp
1
140-142 °C; Yield 62%; IR ν (cm-1): 1574 (C=N), 1332 (SO2), 1262 (C-N), 1008 (C-O); 653 (C-Br), H
NMR (300 MHz, CDCl3) δ ppm: 1.19-1.82 (m, 10H), 1.96-2.16 (m, 2H), 2.25-2.32 (m, 2H), 2.73-2.79
(m, 2H), 3.56-3.72 (m, 4H), 4.26-4.34 (m, 1H), 7.57-7.60 (d, J=8.62 Hz, 2H), 7.67-7.70 (d, J=8.62 Hz,
2H);13C NMR (75 MHz, CDCl3) δ ppm: 24.22, 26.06, 27.40, 29.98, 38.96, 50.55, 51.50, 66.86, 113.98,
127.20, 128.50, 131.99, 139.60, 145.83.
N-(Cycloheptyl(morpholino)methylene)-4-iodobenzenesulfonamide (5j). White solid. mp 160-162 °C;
1
Yield 78%; H NMR (300 MHz, DMSO) δ ppm: 1.11-2.90 (m, 10H), 2.08-2.12 (m, 2H), 3.37 (s, 8H),
13
4.43-4.51 (m, 1H), 7.57 (d, J=8.53 Hz, 2H), 7.68 (d, J=8.53 Hz, 2H), C NMR (75 MHz, DMSO) δ ppm:
23.84, 26.34, 27.30, 28.05, 29.00, 30.45, 49.52, 49.52, 50.58, 65.69, 99.62, 128.26, 137.42, 141.44, 145.75.
N-(Cycloheptyl(morpholino)methylene)thiophene-2-sulfonamide (5k). White solid. mp 142-144 °C;
Yield 51%; IR ν (cm-1): 1539 (C=N), 1330 (SO2), 1249 (C-N), 1015 (C-O); 1H NMR (300 MHz, CDCl3) δ
ppm: 1.20-2.13 (m, 12H), 2.29-2.36 (m, 1H), 2.74-2.81 (m, 1H), 3.60-3.71 (m, 6H), 4.31-4.38 (m, 1H),
6.97-7.05 (m, 1H), 7.52-7.57 (m, 2H); 13C NMR (75 MHz, CDCl3) δ ppm: 24.23, 25.99, 27.85, 28.17, 29.94,
30.11, 43.38, 51.57, 51.84, 66.41, 66.88, 127.11, 129.95, 131.67, 131.67, 141.30, 146.09. Anal. Calcd for
C16H24S2O3N2 (%): C 54.26, H 6.79, N 7.82, S 17.81. Found C 54.05, H 6.79, N 7.78, S 18.04; HRMS
(ESI) calcd. for C16H24S2O3N2 ([M+H]+) 357.1301. Found 357.1301.
ACKNOWLEDGEMENTS
The authors cordially thank Professor J.-M. Pons (Institute of Molecular Science of Marseille (ism2) of
Aix-Marseille University, Faculty of Sciences) for centesimal analysis and the mass spectra.
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